This invention provides novel compositions of matter.
Particularly this invention provides novel lactones of some of the known prostaglandins or prostaglandin analogs.
The known prostaglandins include the PGE compounds, e.g. prostaglandin E.sub.1 (PGE.sub.1), prostaglandin E.sub.2 (PGE.sub.2), prostaglandin E.sub.3 (PGE.sub.3), and dihydroprostaglandin E.sub.1 (dihydro-PGE.sub.1).
The known prostaglandins include PGF.sub..alpha. compounds, e.g. prostaglandin F.sub.1.alpha. (PGF.sub.1.alpha.), prostaglandin F.sub.2.alpha. (PGF.sub.2.alpha.), prostaglandin F.sub.3.alpha. (PGF.sub.3.alpha.), and dihydroprostaglandin F.sub.1.alpha. (dihydro-PGF.sub.1.alpha.).
The known prostaglandins include PGF.sub..beta. compounds, e.g. prostaglandin F.sub.1.beta. (PGF.sub.1.beta.), prostaglandin F.sub.2.beta. (PGE.sub.2.beta.), prostaglandin F.sub.3.beta. (PGE.sub.3.beta.), and dihydroprostaglandin F.sub.1.beta. (dihydro-PGF.sub.1.beta.).
The known prostaglandins include PGA compounds, e.g. prostaglandin A.sub.1 (PGA.sub.1), prostaglandin A.sub.2 (PGA.sub.2), prostaglandin A.sub.3 (PGA.sub.3), and dihydroprostaglandin A.sub.1 (dihydro-PGA.sub.1).
the known prostaglandins include PGB compounds, e.g. prostaglandin B.sub.1 (PGB.sub.1), prostaglandin B.sub.2 (PGB.sub.2), prostaglandin B.sub.3 (PGB.sub.3), and dihydroprostaglandin B.sub.1 (dihydro-PGB.sub.1).
Each of the above mentioned known prostaglandins (PG's) is a derivative of prostanoic acic which has the following structure and carbon atom numbering ##STR1## See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]heptanoic acid.
PGE.sub.1 has the following structure: ##STR2##
PGE.sub.2 has the following structure: ##STR3##
PGE.sub.3 has the following structure: ##STR4##
Dihydro-PGE.sub.1 has the following structure: ##STR5##
PGF.sub.1.alpha. has the following structure: ##STR6##
PGF.sub.2.alpha. has the following structure: ##STR7##
PGF.sub.3.alpha. has the following structure: ##STR8##
Dihydro-PGF.sub.1.alpha. has the following structure: ##STR9##
PGF.sub.1.beta. has the following structure: ##STR10##
PGF.sub.2.beta. has the following structure: ##STR11##
PGF.sub.3.beta. has the following structure: ##STR12##
Dihydro-PGF.sub.1.beta. has the following structure: ##STR13##
PGA.sub.1 has the following structure: ##STR14##
PGA.sub.2 has the following structure: ##STR15##
PGA.sub.3 has the following structure: ##STR16##
Dihydro-PGA.sub.1 has the following structure: ##STR17##
PGB.sub.1 has the following structure: ##STR18##
PGB.sub.2 has the following structure: ##STR19##
PGB.sub.3 has the following structure: ##STR20##
Dihydro-PGB.sub.1 has the following structure: ##STR21##
In the above formulas, as well as in the formulas hereinafter given, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachment in a mixture of alpha and beta configurations.
The side-chain hydroxy at C-15 in the above formulas is in S configuration. See, Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins. Expressions such as C-9, C-11, C-15, and the like, refer to the carbon atom in the prostaglandin analog which is in the position corresponding to the position of the same number in prostanoic acid.
Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. As drawn, the above formulas each represent the particular optically active form of the prostaglandin as is obtained from mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, from carbonyl and/or double bond reduction of the prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of these formulas represents the other enantiomer of that prostaglandin. The racemic form of a prostaglandin contains equal numbers of both enantiomeric molecules, and one of the above formulas and the mirror image of that formula is needed to represent correctly the corresponding racemic prostaglandin.
For convenience hereinafter, use of the term, prostaglandin or "PG" will mean the optically active form of that prostaglandin thereby referred to with the same absolute configuration as PGE.sub.1 obtained from mammalian tissues. When reference to the racemic form of one of those prostaglandins is intended, the word "racemic" or "d1" will precede the prostaglandin name.
The term "prostaglandin-type" (PG-type) compound, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes as the prostaglandins, as indicated herein.
The term prostaglandin-type intermediate, as used herein, refers to any cyclopentane derivative useful in preparing a prostaglandin-type compound.
The formulas, as drawn herein, which depict a prostaglandin-type compound or an intermediate useful in preparing a prostaglandin-type compound, each represent the particular stereoisomer of the prostaglandin-type compound which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostaglandin-type compounds.
The term "prostaglandin analog", as used herein, represents that stereoisomer of a prostaglandin-type compound which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, a mixture comprising that stereoisomer and the enantiomer thereof, or the enantiomer thereof. In particular, where a formula is used to depict a prostaglandin- type compound herein, the term prostaglandin analog refers to the compound of that formula, or a mixture comprising that compound and the enantiomer thereof.
The term "prostaglandin-type lactone" as used herein refers to a 1,9-; 1,11-; or 1,15-lactone of a prostaglandin or prostaglandin analog, but only to the extent that the C-9, C-11, or C-15 position, respectively, is hydroxylated and thus capable of lactone formation with the PG carboxyl. For example, as applied to a PGE-type compound (e.g. PGE.sub.2) the term "prostaglandin-type lactone" refers only to a 1,11- or 1,15-lactone. Further, where a formula is used to depict a prostaglandin-type lactone herein, or a prostaglandin analog from which the prostaglandin-type lactone is prepared, the term "prostaglandin-type lactone" refers to the compound of that formula (or the lactone prepared therefrom) or a mixture comprising that compound (or the lactone prepared therefrom) and the enantiomer thereof.
The various PG's named above, their esters, acylates and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein.
For the PGE compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests, for example, on guinea pig ileum, rabbit duodenum, or qerbil colon); PA1 b. affecting lipolytic activity (as shown by antagonism of epinephrine induced release of glycerol from isolated rat fat pads); PA1 c. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors; PA1 d. controlling spasm and facilitating breathing in asthmatic conditions; PA1 e. decongesting nasal passages; PA1 f. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ATP, ADP, serotinin, thrombin, and collagen); PA1 g. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle; and PA1 h. accelerating growth of epidermal cells and keratin in animals. PA1 a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); PA1 b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors; PA1 c. decongesting nasal passages; PA1 d. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen); and PA1 e. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstral cycle. PA1 a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); PA1 b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors; PA1 c. controlling spasm and facilitating breathing in asthmatic conditions; PA1 d. decongesting nasal passages; PA1 e. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombis formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen); and PA1 f. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle. PA1 a. stimulating smooth muscle (as shown by tests on quinea pig ileum, rabbit duodenum, or gerbil colon); PA1 b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors; PA1 d. controlling spasm and facilitating breathing in asthmatic conditions; PA1 d. decongesting nasal passages; and PA1 e. increasing kidney blood flow. PA1 a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); and PA1 b. accelerating growth of epidermal cells and keratin in animals. PA1 wherein W.sub.2 is ##STR78## PA1 L.sub.1, m.sub.1, y.sub.1, and R.sub.7 are as defined above. PA1 R.sub.8 is hydrogen or hydroxy. PA1 R.sub.9 is an acyl protecting group. PA1 R.sub.10 is a blocking group. PA1 R.sub.33 is --O--Si--(G.sub.1).sub.3 wherein G.sub.1 is alkyl, cycloakyl, aralkyl, phenyl, or phenyl substituted with alkyl or halogen, the various G.sub.1 's of a --Si--(G.sub.1).sub.3 moiety being the same or different. PA1 Z.sub.4 is ##STR83## wherein T and s are as defined above, and
For the PGF.sub..alpha. compound these biological responses include:
For the PGF.sub..alpha. compounds these biological response include:
For the PGA compounds these biological responses include:
For the PGB compounds these biological responses include:
Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
The compounds so cited above as extremely potent in causing stimulation of smooth muscle are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore, these compounds for example, are useful in place of or in combination wth less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the prostaglandin is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50.mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.
As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g. diabetes mellitus, vascular diseases, and hyperthyroidism.
The prostaglandins so cited above as useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secetion, therby reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 to about 500 .mu.g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
these compounds are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the prostaglandin and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE.sub.1, PGE.sub.2, PGE.sub.3, 13,14-dihydro-PGE.sub.1, and the corresponding 11-deoxy-PGE and PGA compounds. Prostaglandins are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge et al. as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.
The anti-flammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.
The prostaglandin is administered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the anti-inflammatory substance is being administered orally, the prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as described in U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostaglandin is also administered rectally, or, alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and prostaglandin, to combine both into a single dosage form.
The dosage regimen for the prostaglandin in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effects, and the particular prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experienced the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the prostaglandin to reduce and then substantially to eliminate those undesirable effects.
The prostaglandins so cited above as useful in the treatment of asthma, are useful, for example, as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia, and emphysema. For these purposes, the compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally; subcutaneously; or intramuscularly; with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.1 to 5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these prostaglandins can be combined advantageously with other antiasthmatic agents, such as sympathomimerics (isoproterenol, phenylephrine, epinephrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone). Regarding use of these compounds see M. E. Rosenthale, et al., U.S. Pat. No. 3,644,638.
The prostaglandins so cited above as useful in mammals, including man, as nasal decongestants are used for this purpose, in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
The prostaglandins so cited above as useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
These compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
The prostaglandins so cited above as useful in place of oxytocin to induce labor are used in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.
These compounds are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the prostaglandin is administered systemically at a dose level in the range 0.01 to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first or second trimester of the normal mammalian gestation period.
These compounds are further useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful in diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the prostaglandin is administered locally or systemically.
The prostaglandin, for example, is administered orally or vaginally at doses of about 5 to 50 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. Alternatively the prostaglandin is administered intramuscularly or subcutaneously at doses of about one to 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.
These compounds are further useful in domestic animals as an abortifacient (especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchronization of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both conception and labor by enabling the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher percentage of live births than the percentage achieved by natural control. The prostaglandin is injected or applied in a feed at doses of 0.1-100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the species treated. For example, mares are given the prostaglandin 5 to 8 days after ovulation and return to estrus. Cattle, are treated at regular intervals over a 3 week period to advantageously bring all into estrus at the same time.
The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal dysfunction, especially those involving blockage of the renal vascular bed. Illustratively, the PGA compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the PGA compounds are preferably first administered by intravenous injections at a dose in the range 10 to 1000 .mu.g. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 .mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.
The compounds so cited above as promoters and acceleraters of growth of epidermal cells and keratin are useful in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals for this purpose. For this reason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
For the above purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration in advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate, a wet dressing for topical application to second and/or third degree burns of skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing 1 to 500 .mu.g. per ml. of the prostaglandin pound. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymixin, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combination at the usual concentration suitable for its use alone.
In addition to the discovery of the prostaglandins cited above, various prostaglandin analogs have likewise been discovered. In particular, there are known prostaglandin analogs of the formula ##STR22## wherein D is ##STR23## wherein R.sub.8 is hydrogen or hydroxy;
wherein L.sub.1 is ##STR24## or a mixture of ##STR25## and ##STR26## wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro, only when the other is hydrogen or fluoro;
wherein M.sub.1 is ##STR27## or ##STR28## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is one to 5, inclusive, cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, or ##STR29## wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z.sub.3 is oxa or methylene, with the proviso that not more than two T's are other than alkyl, and the further proviso that Z.sub.3 is oxa only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is EQU cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, (1) EQU cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --, (2) EQU cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, (3) EQU --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CH.sub.2 --, (4) EQU --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CF.sub.2 --, (5) EQU --ch.sub.2 --o--ch.sub.2 --(ch.sub.2).sub.g --CH.sub.2 --, (6) ##STR30## wherein g is one, 2, or 3.
While the use and preparation of many of the prostaglandin analogs described above is widely known in the art, the Appendix, hereto provides a discussion of the preparation of each of the various compounds depicted by formula I above.
For the prostaglandin analogs described in formula I above, a convenient classification system according to cyclopentane ring structure is effected by referencing:
a. PGF.sub..alpha. -type compounds when D is ##STR31##
b. 11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR32##
c. PGE-type compounds when D is ##STR33##
d. 11-deoxy-PGE-type compounds when D is ##STR34##
e. PGF.sub..beta. -type compounds when D is ##STR35##
f. PGD-type or 9.beta.-PGD-type compounds when D is ##STR36## and
g. 9-deoxy-PGD-type compounds when D is ##STR37##
h. 9-deoxy-9,10-didehydro-PGD-type compounds when D is ##STR38## and
i. PGA-type compounds when D is ##STR39##
j. PGB-type compounds when D is ##STR40##
k. 8.beta.,12.alpha.-PGF.sub..alpha. -type compounds when D is ##STR41##
l. 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR42##
m. 8.beta.,12.alpha.-PGE-type compounds when D is ##STR43##
n. 8.beta.,12.alpha.-11-deoxy-PGE-type compounds when D is ##STR44##
o. 8.beta.,12.alpha.-PGF.sub..beta. -type compounds when D is ##STR45##
p. 8.beta.,12.alpha.-PGD-type or 8.beta.,9.beta.,12.alpha.-PGD-type compounds when D is ##STR46##
q. 8.beta.,12.alpha.-9-deoxy-PGD-type compounds when D is ##STR47## and
s. 8.beta.,12.alpha.-PGA-type compounds when D is ##STR48##
Those prostaglandin analogs wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- or cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 -- are named as "PG.sub.2 " compounds. The latter compounds are further characterized as "2,2-difluoro" PG.sub.2 -type compounds. When g is 2 or 3, the prostaglandin analogs so described are "2a-homo" or "2a,2b-dihomo" compounds, since in this event the carboxy terminated side chain contains 8 or 9 carbon atoms, respectively, in place of the 7 carbon atoms contained in PGE.sub.1. These additional carbon atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly, these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.
Further when Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 -- or --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2, wherein g is as defined above, the PG analogs so described are "PG.sub.1 " compounds. When g is 2 or 3, the "2a-homo" and "2a, 2b-dihomo" compounds are described as is discussed in the preceding paragraph.
When Z.sub.1 is --CH.sub.2 13 0--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- the PG analogs so described are named as "5-oxa-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are "2a-homo" or "2a, 2b-dihomo" compounds, respectively, as discussed above.
When Z.sub.1 is cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, wherein g is as defined above, the PG analogs so described are named "cis-4,5-didehydro-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are further characterized as "2a-homo" or "2a,2b-dihomo" compounds, respectively, as discussed above.
For the PG analogs wherein Z.sub.1 is ##STR49## there are described, respectively, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor or 3,7-inter-m-phenylene-4,5,6-trinor-PG-type compounds, when g is one. When g is 2 or 3, the above compounds are additionally described as "2a-homo" or "2a,2b-dihomo" PG-type compounds, respectively.
The prostaglandin analogs described herein which contain a cis--CH.dbd.CH-- moiety at the C-13 to C-14, the compounds so described are "13-cis" compounds.
Further when the C-13 to C-14 moiety is --C.tbd.C-- or --CH.sub.2 CH.sub.2 -- the compounds so described are named as "13,14-didehydro" or "13,14-dihydro" compounds, respectively.
When R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is as defined above, the PG analogs so described are named as "19,20-dinor", "20-nor", "20-methyl", or "20-ethyl" compounds when m is one, 2,4, or 5, respectively. When R.sub.7 is ##STR50## wherein T and s are as defined above, the PG analogs so described are named as "17-phenyl-18,19,20-trinor" compounds, when s is 0. When s is one, 2, or 3, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor" compounds.
When R.sub.7 is ##STR51## wherein T and s are as defined above, and neither R.sub.3 nor R.sub.4 is methyl, the PG analogs so described are named as "16-phenoxy-17,18,19,20-tetranor" compounds, when s is zero. When s is one, 2, or 3, the corresponding compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R.sub.3 and R.sub.4 is methyl or both R.sub.3 and R.sub.4 are methyl, then the corresponding compounds wherein R.sub.7 is as defined in this paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or "16-methyl-16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds, respectively.
When R.sub.7 is cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, the compounds so described are "PG.sub.3 " or "cis-17,18-didehydro" compounds depending on whether Z.sub.1 is cis--CH.dbd.CH--(CH.sub.2).sub.g --C(R.sub.2).sub.2, wherein R.sub.2 is hydrogen or fluoro, or another moiety, respectively.
When at least one of R.sub.3 and R.sub.4 is not hydrogen then (except for the 16-phenoxy compounds discussed above) there are described the "16-methyl" (one and only one of R.sub.3 and R.sub.4 is methyl), "16,16-dimethyl" (R.sub.3 and R.sub.4 are both methyl), "16-fluoro" (one and only one of R.sub.3 and R.sub.4 is fluoro), "16,16-difluoro" (R.sub.3 and R.sub.4 are both fluoro) compounds. For those compounds wherein R.sub.3 and R.sub.4 are different, the prostaglandin analogs so represented contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: "(16S)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16RS)".
When R.sub.5 is methyl, the compounds so described are named as "15-methyl" compounds.
Some formulas of 13-cis-cyclopentane derivatives described hereinafter contain a moiety of the formula: ##STR52## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein; wherein L.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.4 is cis--CH.dbd.CH--. Optionally the above formula is depicted with one or both of L.sub.1 and M above the carbon atom to which it is attached, e.g., as follows: ##STR53## When either of the above representations is employed, it is hereby defined to indicate the following convention with respect to the representation of the cis-13 double bond: ##STR54## Further in employing this convention when M is, for example, ##STR55## or ##STR56## then the corresponding representations: ##STR57## or ##STR58## are intended, respectively. Accordingly all the formulas herein which represent 13-cis cyclopentane derivatives are depicted by the same convention as that for the cis-13-PGE.sub.1 when drawn as follows: ##STR59## Thus, by this convention the (15S)-hydroxy of cis-13-PGE.sub.1 is in the beta configuration.
cis-13-PG-type compounds as drawn herein which have an hydroxy or methoxy at C-15 in the alpha configuration are of the opposite relative stereochemical configuration at C-15 as that of cis-13-PGE.sub.1, and are therefore named as "15-epi" compounds. When the beta hydroxy or methoxy configuration is present, no special designation of this stereochemistry is provided.
Accordingly, 15-epi-16,16-difluoro-cis-13-PGD.sub.2 is depicted herein as follows: ##STR60##
Alternate representations of cis-13-PGE.sub.1 affect the depiction of C-15 as an alpha or beta hydroxy. Thus, by a representation contrary to the instant convention, cis-13-PGE.sub.1 appears as follows: ##STR61##
Accordingly, care must be taken to consistently draw the formulas of cis-13-PG-type compounds herein such that the C-15 carbon atoms is properly represented, i.e., all cis-13-15-epic-PG's are of the 15.alpha.-hydroxy configuration.
13,14-trans-13,14-dihydro, or 13,14-didehydro cyclopentane derivatives which contain the moiety ##STR62## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein; wherein L.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.3 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or --C.tbd.C-- respectively. When this representation is employed, it is hereby defined to indicate the following convention with respect to the representation of the C-13 to C-14 moiety: ##STR63## or ##STR64## respectively. Likewise in employing this convention when M is, for example ##STR65## or ##STR66## then the corresponding representation for the trans-13 compounds: ##STR67## or ##STR68## the 13,14-dihydro compounds: ##STR69## or ##STR70## and the 13,14-didehydro compounds: ##STR71## or ##STR72## are intended, respectively. Accordingly all the formulas herein which represent trans-13, 13,14-dihydro, or 13,14-didehydro-cyclopentane derivatives are depicted by the same convention as that for PGE.sub.1 when drawn as above, i.e., ##STR73##
Thus, for all trans-13, 13,14-dihydro, or 13,14-didehydro-PG-type compounds, as drawn herein the 15.alpha.-hydroxy configuration corresponds to the relative C-15 stereochemical configuration of PGE.sub.1 as obtained from mammalian tissues. No special designation of the C-15 stereochemistry is provided in naming these compounds. For compounds of the opposite stereochemical configuration at C-15 (i.e., 15.beta.-hydroxy), the description "15-epi" will be employed.
The prostaglandin analogs of formula I are known to correspond to the prostaglandins described above, in that these prostaglandin analogs exhibit prostaglandin-like activity.
Specifically the PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and 11-deoxy-PGE-type compounds correspond to the PGE compounds described above, in that these PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and 11-deoxy-PGE-type compounds are useful for each of the above-described purposes for which the PGE compounds are used, and are used in the same manner as the PGE compounds, as described above.
The PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds correspond to the PGF.sub..alpha. compounds described above, in that these PGF.sub.60 -, 8.beta.,12.alpha.-PGF.sub..alpha., 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds are useful for each of the above-described purposes for which the PGF.sub..alpha. compounds are used, and are used in the same manner as the PGF compounds, as described above.
The PGD-, 9.beta.-PGD-, 8.beta.,12.alpha.-PGD-, 8.beta.,9.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9,10-didehydro-9-deoxy-PGD-, and 9,10-didehydro-9-deoxy-PGD-type compounds of formula I correspond to the PGE or PGF.sub..alpha. compounds described above, in that these PGD-, 8.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-9,10-didehydro-PGD-, or 9-deoxy-9,10-didehydro-PGD-type compounds are useful for each of the above-described purposes for which either the PGE or PGF.sub..alpha. compounds are used, and are used in the same manner as the PGE and PGF.alpha. compounds, as described above.
The PGA- or 8.beta.,12.alpha.-PGA-type compounds of formula I correspond to the PGA compounds described above, in that these PGA- or 8.beta.,12.alpha.-PGA-type compounds are useful for each of the above described purposes for which the PGA compounds are used, and are used in the same manner as the PGA compounds, as described above. The PGB-type compounds of formula I correspond to the PGB compounds described above in that the PGB compounds are useful for each of the above described purposes for which PGB compounds are used, and are used in the same manner as the PGB compounds described above.
The prostaglandins described above, ar all known to be potent in causing multiple biological responses even at low doses. Moreover, for many applications, there prostaglandins are known to exhibit a relatively short duration of biological activity. Significantly, the prostaglandin analogs of formula I are known to be substantially more selective with regard to potency in causing prostaglandin-like biological responses, and have a somewhat longer duration of biological activity. Thus, each of these prostaglandin analogs is known to be equally or even more useful than one of the corresponding prostaglandins described above for at least one of the pharmacological purposes indicated above for the latter.
Another property of the prostaglandin analogs of formula I, compared with the corresponding prostaglandins, is that these PG analogs are known to be capable of effective administration orally, sublingually, intravaginally, buccally, or rectally in many cases where the corresponding prostaglandin is known to be effective only by the intravenous, intramuscular, or subcutaneous injection or infusion methods of administration indicated above as used of these prostaglandins. When alternate routes of administration are employed, they are known to facilitate maintaining unilevels of these compounds in the body with fewer, shorter, or smaller doses, and to make possible self-administration by the patient.
Accordingly, the prostaglandin analogs of formula I are known to be capable of administration in various ways for various purposes: e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action. For intravenous injection or infusion, sterile aqueous isotonic solutions are known to be preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, the use of sterile tablets or silicone rubber capsules or other objects containing or impregnated with the substance is known.
Methods for the preparation of large ringed lactones are known in the art. See, for example, E. J. Corey, et al., Journal of the American Chemical Society 96: 5614 (1974). Further, certain 1,9 lactones of cyclopentane containing carboxylic acids are known in the art. See Sourth African Application No. 737,357, Derwent Farmdoc CPI No. 28414V, which discloses 1,9-lactones of .mu.-heterocyclic prostaglandin analogs; Japanese Application No. 50-0037-793, Derwent Farmdoc CPI No. 61147W, which discloses 15-deoxy-15-methyl-PGF.sub.2.alpha., 1,9-lactone; and E. J. Corey, et al., Journal of the American Chemical Society 97: 653 (1975), which discloses PGF.sub.2.alpha. 1,9-lactone. Further, the latter reference additionally discloses PGF.sub.2.alpha., 1,15-lactone.
Finally, see Japanese Patent Application No. 50013-385, Derwent Farmdoc CPI No. 56267W, which discloses 1,9lactones of PGF.sub.2.alpha. and (15RS)-15-methyl-PGF.sub.2.alpha..